There are two types of retinoids, those that are naturally produced in all living organisms and those known as synthetic retinoids. Natural retinoids are found in all living organisms either as Vitamin A or carotenoids (6). These two types of retinoids are essential for numerous biological processes such as vision, cellular growth and differentiation, and reproduction (6). Synthetic retinoids like isotretinoin, etretinate, and bexarotene are all used to treat people with certain types of skin diseases (3).
Natural retinoids such as retinol (Vitamin A) are synthesized into retinaldehyde and then to all-trans retinoic acid via two oxidation steps (2, 7). The first oxidation step involves the synthesis of retinol to retinaldehyde by means of alcohol dehydrogenase and short-chain dehydrogenase enzymes. The second step involves retinaldehyde to all-trans retinoic acid via three retinaldehyde dehydrogenase enzymes (2, 7). These all-trans retinoic acid is converted to hydroxylated metabolites by cytochrome P 450 enzyme (Cyp 26). This metabolite is critical in developing mice embryos since it protects tissues from inappropriate exposure to all-trans retinoic acid (2, 7).
Synthetic retinoids are derived from retinol (Vitamin A) (4). Although there are several kinds of synthetic retinoids, each was made to perform specific functions in the body (4). Synthetic retinoids were produced to mimic the actions of certain natural retinoids. This was done because the natural retinoids either had severe side effects or different transport mechanisms. For example, when large amounts of natural retinoids are ingested during a meal, it can be highly toxic (4).
The mechanism for natural and synthetic retinoids involves two types of nuclear retinoid receptors; the retinoic acid (RA) receptor and the retinoid X receptor. Both receptors are coded for by three genes (α, β, and γ) from which multiple receptor isoforms can be produced (1). RARs bind and are activated by tRA and 9-cis-RA, whereas RXRs only interact with 9-cis-RA. These receptors mediate retinoid signals by binding to specific DNA sequences or RA responsive elements as RAR-RXR heterodimers or homodimers or by interacting with other transcriptional factors (1). Not only are the RXRs critical for allowing effective binding of the RARs to DNA but it also increases DNA binding to other receptors that work together with different hormones or vitamin derivatives. Thus the RXRs play a vital role in mediating a variety of hormonal signals in the nucleus (1).
Bexarotene (Targretin®) is a pharmaceutical drug used to treat cutaneous T-cell lymphoma as well as off label to treat other types of cancer. Bexarotene is a synthetic retinoid analog with specific affinity for retinoid X receptors (6). Bexarotene is currently an FDA approved drug, effective in the treatment of cutaneous T-cell lymphoma (CTCL), and it is being explored for treatment of breast cancer, lung cancer, colon cancer, and other diseases of uncontrolled cellular proliferation, because activation of RXR and “up-regulation” (or expression) of the genes regulated by RXR seems to have a therapeutic effect by slowing or arresting cellular proliferation in these conditions. Bexarotene and one of its analogs have also been explored as possible treatments for noninsulin-dependent diabetes mellitus (NIDDM) in mouse models. Despite bexarotene's specific activation of RXR, versus RAR, three drawbacks to the use of bexarotene include hypothyroidism, since there may be an unintentional antagonism of the TR receptor with ligand activated RXR39, hyperlipidemia, and cutaneous toxicity as a possible result of residual RAR agonism at the dose concentration. There is also evidence that bexarotene regulates the expression of pyruvate dehydrogenase kinase (PDK4) in the heart. Thus, there is a need to prepare analogues of bexarotene that are specific only for the RXR homodimer such that the therapeutic effects of the bexarotene of inhibiting cell proliferation and treatment of various cancers can be realized without the concomitant detrimental effects of hypothyroidism.